Clonal Evolution and Genomic Stability as Endpoints of Chemoprevention: Evidence from WES Studies

Abstract

Cancer chemoprevention has historically relied on clinical endpoints (tumor incidence, survival) as measures of efficacy, requiring decades of follow-up and large patient cohorts. Whole-exome sequencing-enabled molecular monitoring of clonal evolution and genomic stability now offers mechanistic alternatives enabling real-time assessment of whether chemopreventive agents successfully suppress high-risk clones or inadvertently select for resistant populations. This comprehensive review synthesizes evidence that clonal evolution dynamics measured through circulating cell-free DNA (cfDNA) monitoring, subclonal architecture reconstruction, and variant allele frequency changes represent sensitive, biologically-meaningful endpoints of chemoprevention efficacy. We examine how WES reveals whether prevention agents achieve true elimination of transformative clones versus mere delay of inevitable progression, a critical distinction with different clinical implications. Suppression of high-risk clones carrying driver mutations (TP53, NOTCH1, PIK3CA) is discussed alongside mechanisms including genomic instability enhancement, immune checkpoint activation, and senescence induction. Integration of clonal evolution endpoints with genomic stability assessment quantified through measures including mutational burden dynamics, copy number variation stability, and DNA repair gene expression provides comprehensive evaluation of chemoprevention-induced evolutionary constraints. Case studies demonstrate successful clonal suppression in chronic lymphocytic leukemia under targeted therapy, osimertinib-resistant lung cancer clones under combination approaches, and emerging oral dysplasia suppression through immune checkpoint blockade. Critical challenges including distinguishing adaptive clonal responses from true suppression, heterogeneity in clonal fitness landscapes, and translating molecular suppression to clinical benefit are addressed. The review discusses adaptive trial designs leveraging clonal evolution endpoints, mathematical modeling of clonal evolutionary trajectories, and future integration with spatial transcriptomics and single-cell technologies enabling unprecedented resolution of prevention mechanisms.